Management of Pulmonary Neuroendocrine Tumors | 13 |
INTRODUCTION
Pulmonary neuroendocrine tumors (NETs) are a spectrum of lung malignancies that arise from the neuroendocrine (NE) cells of the bronchopulmonary epithelium (1). The term encompasses a wide range of clinicopathological traits and biologic behaviors; at one end of the spectrum are low-grade, slow-growing tumors, while at the other end are high-grade, aggressive tumors. Several classification schemes have been developed to describe these differing entities, all encompassed by the broad category of NET. In this chapter, we focus on the management of well-differentiated neuroendocrine tumors (WD-NET), a term that includes typical and atypical carcinoid (AC) tumors, and poorly differentiated large-cell neuroendocrine carcinoma (LCNEC). Small-cell lung cancer (SCLC), another high-grade, poorly differentiated NET, is covered in detail in Chapters 10 and 11.
CLASSIFICATION AND EPIDEMIOLOGY
Well-Differentiated Pulmonary NETs
WD-NETs, also called bronchopulmonary carcinoids (BPC), are rare tumours originating from the lung. WD-NETs can be further subclassified into low-grade typical carcinoids (TC), accounting for 90% of BPCs, and intermediate-grade AC, accounting for 10% of BPCs (Table 13.1) (2). Pulmonary WD-NETs are estimated to account for 1% to 2% of all adult lung malignancies and the incidence has increased over the last 30 years by approximately 6% per year (3). Potential explanations for this increasing incidence include higher sensitivity of detection by improved imaging techniques and a more specific diagnostic classification. Overall, the incidence rate ranges between 0.2 and 2 per 100,000 people per year (4). Approximately, 5% of pulmonary WD-NETs are associated with multiple endocrine neoplasm type 1 (MEN1) (5). WD-NETs more commonly arise in the gastrointestinal (GI) tract, with GI NETs accounting for two-thirds of all WD-NETs. It is not uncommon for both GI and pulmonary NETs to be included within the same clinical trial, a practice that confounds the development of appropriate treatment algorithms since WD-NETs occurring in different locations do not always exhibit the same biological behavior or response to specific therapy.
Large-Cell Neuroendocrine Carcinoma
LCNEC is a high grade, poorly differentiated NET that has only been recognized as a distinct NET over the past 25 years (6,7). LCNEC is distinguished from other large cell carcinomas by NE cellular differentiation and histologic architecture, and from WD-NETs by its higher mitotic rates, worse prognosis, and more aggressive behavior (Table 13.1). Histologically, LCNEC shares the qualities of poor differentiation and higher grade with SCLC, but is distinguished from SCLC by larger cell size. LCNEC accounts for approximately 3% of lung malignancies, but many aspects of this entity remain unclear given its low incidence and relatively recent classification (4).
CLINICAL PRESENTATION
Tumor Location
The majority of pulmonary NETs arise within the central airways of the lung, and because of this location approximately 60% of patients present with dyspnea, hemoptysis, cough, pneumonia, chest discomfort, and/or unilateral wheezing. Peripheral pulmonary NETs are usually asymptomatic and are commonly discovered incidentally (5).
Secretory Tumors
Hormonally active pulmonary NETs are much less common than their GI counterparts, and are rarely diagnosed at an early stage. Only 1% to 2% of patients with pulmonary NETs present with symptoms associated with classic carcinoid syndrome, such as flushing, diarrhea, wheezing, and right-sided valvular heart disease (2,5,8). Patients should be monitored for carcinoid crisis following radiotherapy or procedural manipulation, but the risk is low enough that routine prophylaxis with a somatostatin analogue (SSA) is not recommended. Another 1% to 6% of patients with pulmonary NETs present with Cushing syndrome caused by ectopic adenocorticotrophic hormone (ACTH) production, with symptoms such as new onset glucose intolerance, proximal myopathy, hirsutism, facial plethora, and/or centripetal obesity. Though hormonal production is uncommon, all patients with pulmonary NETs should be clinically screened for paraneoplastic syndromes, with further laboratory and radiographic evaluation based on clinical suspicion (8,9).
DIAGNOSIS AND EVALUATION
Imaging
The European Neuroendocrine Tumor Society (ENETS) recommends the use of contrast CT as the gold standard for detecting pulmonary NETs (9). Complete staging should include a preoperative CT of the chest, abdomen, and pelvis for patients with potentially resectable disease. For those with metastatic disease, directed imaging with multiphasic CT or MRI is recommended for further elucidation of possible metastases, particularly to the liver (9).
Based on small retrospective studies, fluorodeoxyglucose-positron emission tomography (FDG-PET) has limited use in the detection of primary or metastatic WD-NETs due to their low metabolic activity (10). In contrast, LCNECs have much higher uptake of FDG with a usual mean standardized uptake value (SUV) of 9 to 12, which is comparable to that of SCLC. Therefore, FDG-PET can be useful in staging patients with LCNEC (5).
Indium-111 pentetreotide scintigraphy (octreotide scan) can be used to detect somatostatin subtype receptors (SSTR) on WD-NETs, although its routine use is not universally recommended (5).
Other Diagnostic Modalities
Patients with pulmonary NETs who are potentially eligible for curative resection must undergo a thorough preoperative clinical assessment to fully define tumor histology, location, and stage, as well as perioperative risk (8). For tumors in the central portion of the lung, a full workup includes bronchoscopy, potentially with endobronchial ultrasound-guided evaluation of mediastinal lymph nodes. Patients presenting with carcinoid syndrome or potential cardiovascular compromise should be considered for echocardiography. Pulmonary function tests should also be obtained prior to surgery, especially in high-risk patients such as those with preexisting lung disease (9).
Laboratory Investigations
Baseline biochemical investigations should be performed on all patients diagnosed with a pulmonary NET. This includes assessment of renal function, liver enzymes, calcium, glucose, and a plasma chromogranin A level. Paraneoplastic syndromes should be investigated if clinical assessment is suspicious for a hormonally secretory tumor. Potentially useful tests include a 24-hour urine for 5-hydroxy-indole-acetic acid (5-HIAA) to evaluate for carcinoid syndrome, and a serum ACTH level for suspected Cushing syndrome. Genetic assessment for MEN1 mutation should only be undertaken if there is a strong suspicion based on family history, or if the patient presents with other features of the MEN1 syndrome (9).
PROGNOSIS
In general, the prognosis of TC is better than AC, and both are considerably better than LCNEC. There are wide variations in survival outcomes within each category of tumor in different reports since patient numbers are generally small. Lewis and Yao analyzed the survival of 187,991 patients with WD-NETs or LCNEC from the Surveillance Epidemiology and End Results (SEER) database and reported that median overall survival duration was 201 months for TC, 101 months for AC, and 6 months for LCNEC. For patients with metastatic disease the 5-year overall survival rates are 40% to 50% for TC, 20% for AC, and <5% for LCNEC (11).
MANAGEMENT OF EARLY STAGE WD-NET
Localized Therapy
For localized TC, due to the more indolent nature of disease, lung-preserving resection using sleeve, wedge, or segmental resection is generally preferred over either more extensive resections or watchful waiting without surgery (8,12). In contrast, a more extensive resection, such as lobectomy or pneumonectomy, is usually required for AC based on its higher incidence of lymph node involvement (30%–70% in AC vs. 5%–20% in TC) (13,14). Full mediastinal lymph node dissection is recommended if initial sampling is positive for lymph node involvement (9,13,14).
Bronchoscopic resection of intraluminal tumor has been studied in small series and has demonstrated good long-term survival for patients with central, endobronchial TC. In one study, of 28 patients who underwent bronchoscopic resection, the 10-year survival rate was 84% (15). However, careful patient selection is crucial, as endobronchial procedures result in a higher rate of recurrence compared to standard lung resections (13).
Stereotactic ablation radiotherapy (SABR) may also be considered for localized stage I pulmonary NETs, particularly in patients who are not good candidates for surgical resection. However, there is minimal data available on the long-term outcomes associated with the use of SABR for pulmonary NETs.
Surveillance Without Treatment
One retrospective series of patients with biopsy-proven, lymph node-negative TC who did not undergo resection reported 5-year disease-specific survival (DFS) rates of 87% for patients with T2 tumors and 92% for those with T1 tumors (12). Thus, careful clinical monitoring without intervention may be a viable option for a small subset of patients with asymptomatic, clinical stage I TC who prefer to avoid therapeutic intervention.
Adjuvant Therapy
Currently, there is a paucity of high-quality evidence addressing the role of adjuvant chemotherapy or radiotherapy in patients with resected WD-NETs. Existing data are primarily from small, retrospective series with many of these reports providing conflicting results.
In TC, the most recent and largest retrospective analysis suggested a trend toward worse 5-year survival rates in patients who underwent adjuvant chemotherapy. In this study, Nussbaum, et al. evaluated data from 629 patients with lymph node-positive TC, of whom 37 underwent adjuvant chemotherapy. Baseline characteristics were similar between those who received chemotherapy and those who did not. The 5-year overall survival rates for the chemotherapy versus no chemotherapy groups were 70% and 82%, respectively (P = .042), although this difference was not statistically significant after propensity matching (P = .096) (16).
Even published guidelines provide no consensus on the utility of adjuvant therapy. For example, ENETS states that only patients with AC and nodal involvement should be considered for adjuvant therapy (9). Similarly, the NCCN supports the use of chemotherapy with or without radiation for resected stage I to III AC and for stage IIIB TC (17). However, the North American Neuroendocrine Tumor Society (NA-NET) does not recommend adjuvant radiotherapy, chemotherapy, or chemoradiation, given the lack of evidence for prolongation of disease-free or overall survival (8).
Recommendations for Early Stage WD-NET
The standard of care in early stage pulmonary NET is complete surgical resection with the goal of R0 resection while maximizing the preservation of lung function. Alternative treatment modalities and surveillance should only be employed in patients who are not surgical candidates or who decide against surgical intervention. Given the lack of evidence of benefit, the routine use of adjuvant chemotherapy cannot be recommended for WD-NETs. However, adjuvant platinum-based chemotherapy could be considered in high-risk individuals on a case-by-case basis, particularly for those with node-positive AC.
Follow-Up After Resection
Disease recurrence occurs mostly within the first 5 years for AC, and first 10 years for TC. Although there is limited evidence that early detection of recurrence changes patient outcomes, given the indolent nature of most WD-NETs, the goal of active surveillance should be to detect recurrences that are amenable to further curative intervention.
Long-term surveillance after local resection is recommended at regular intervals by multiple guideline organizations, though there is no consensus on the timing of investigations (8,9,18). More frequent follow-up is generally recommended in the first year following surgery with chest radiographs and/or CT scans every 3 to 6 months. Subsequently, CT imaging every 1 to 2 years is suggested. If octreotide scan was positive preoperatively, the follow-up scans may be considered at a similar interval. If any biomarkers, such as serum chromogranin A or urinary 5-HIAA were elevated preoperatively, then these should also be followed at regular intervals. The use of other investigations should be guided by clinical findings. In general, AC requires a more intensive follow-up strategy since the recurrence risk is higher. Since WD-NETs are usually indolent in nature, follow-up evaluation is recommended for at least 10 years and could be considered indefinitely.
MANAGEMENT OF METASTATIC WD-NET
Currently, there is no standard international consensus on a step-wise treatment of pulmonary WD-NETs, mainly due to the lack of high-quality clinical evidence to guide treatment decision making. The goals of treatment, however, are clear, to control tumor growth, minimize cancer-related symptoms, improve quality-of-life, and prolong survival. Generally, treatment decisions are made according to prognosis and symptoms (5,9). Good prognostic indicators are TC histology, lack of symptoms, and disease stability over the preceding 6 months. Treatment choices in this group of patients include active surveillance without anticancer therapy, local-regional therapy, and SSAs. Poor prognostic indicators include AC histology, symptomatic disease, and documentation of growth within the last 6 months. Multiple agents have been explored in this group of patients, including targeted therapies, peptide-receptor radiotherapy (PRRT), and palliative chemotherapy.
Traditional Chemotherapy
Few clinical trials have evaluated the use of chemotherapy in pulmonary WD-NETs. As a result, treatment recommendations have been extrapolated from studies in patients with GI NETs and SCLC. Retrospective studies highlight the diversity of treatments that have been used in WD-NETs, including 5-fluoruracil (5FU) plus streptozocin or doxorubicin, cisplatin plus etoposide, and capecitabine plus temozolomide, oxaliplatin, or liposomal doxorubicin (19–21). These studies demonstrate mixed results, with objective responses ranging from 7% to 56%, and median duration of response ranging from 4 to 102 months (Table 13.2). Cisplatin (usually combined with etoposide, as in SCLC) is probably the most commonly used cytotoxic chemotherapy regimen, though responses appear to be substantially higher for patients with AC than with TC. Temozolamide has shown promise as a single-agent with partial responses seen in up to 31% of patients with pulmonary WD-NET (21).
In general, cytotoxic chemotherapy may be considered for symptomatic, bulky, or progressive disease, particularly for patients with AC. Given the small size and mixed results of existing studies, there is no specific chemotherapy regimen that can be recommended, and patient participation in a clinical trial is strongly encouraged.
Targeted Therapy
NETs, including the well-differentiated subtypes, are vascular tumors that often express targetable factors within pathways related to cellular proliferation and angiogenesis (e.g., VEGF/VEGFR, PDGF/PDGFR, IGF1/IGFR) (27). Thus, many targeted antiproliferative agents have been studied, mainly in small clinical trials that included patients with tumors of various subtypes and primary sites (Table 13.2).
MTOR Inhibition
The mammalian target of rapamycin (mTOR) is a kinase that is implicated in cell growth, metabolism, and angiogenesis in NETs. Everolimus is an mTOR inhibitor that has shown the most promising activity in recent trials. RADIANT-4 was a multicenter, randomized, controlled, phase III clinical trial comparing everolimus versus placebo as first- or second-line treatment of nonfunctional NETs of lung or GI origin (22). The study included 90 patients with pulmonary WD-NET, 63 of whom received everolimus. Progression-free survival (PFS) by central review for the entire cohort of NET patients was significantly better in patients treated with everolimus (11 vs. 3.9 months; HR 0.48, 95% confidence interval [CI] 0.35–0.67; P < .00001). For the lung NET cohort, the PFS hazard ratio was 0.50 (95% CI 0.28–0.88) suggesting a significant benefit in disease control. For the whole group, overall survival at the first interim analysis favored the everolimus arm, with a 36% reduction in estimated risk of death compared to placebo. This is the first prospective, randomized trial demonstrating significant PFS benefit in pulmonary WD-NETs. Adverse events were similar to those noted in prior everolimus studies, with stomatitis (63%), diarrhea (31%), and fatigue (13%) being the predominant toxicities. The RADIANT-4 results are consistent with the results of the phase II RAMSETE trial of everolimus in patients with advanced and metastatic, asymptomatic NETs (23). Nineteen patients with bronchial, thymic, or mediastinal NETs were included and everolimus was associated with a median PFS of 6.2 months and stable disease rate of 63%.
Based on this accumulating evidence, we suggest that everolimus be considered for the treatment of incurable pulmonary WD-NETs. In some cases, everolimus is appropriate as a first-line therapy option, particularly for patients whose tumors are somatostatin receptor-negative. In February 2016, the U.S. Food and Drug Administration (FDA) has approved everolimus for the treatment of pulmonary WD-NETs in patients who have advanced or unresectable disease.
Combinations of MTOR Inhibitors Plus Hormonal Therapy
The RADIANT-2, phase III trial randomized 429 patients with hormonally active NETs and carcinoid syndrome to octreotide-LAR with or without everolimus as first- or subsequent-line treatment (28). A subset analysis of the 44 patients with pulmonary WD-NETs demonstrated a median PFS of 13.6 months in the combination arm versus 5.6 months in the octreotide-LAR alone arm, and a “tumour shrinkage” rate (not by RECIST criteria) of 67% for combination therapy versus 27% for octreotide-LAR alone (24).
In a similar trial, 50 patients with advanced NETs (11 with lung primary) were evaluated in the Italian Trials in Medical Oncology (ITMO) Group phase II study to assess octreotide-LAR plus everolimus as first-line therapy. The response rate was 18% (2% with complete response) and the stable disease rate was 74% (25). This suggests a possible role for this combination as first-line treatment in patients with NET. The ongoing LUNA trial is a 3-arm randomized study evaluating everolimus versus pasireotide-LAR versus the combination of both agents as any line of therapy.
Other Targeted Agents
Due to the highly vascular nature of NETs antiangiogenic pathways are an obvious target, but the data from studies of antiangiogenic agents is still preliminary and most responses have been seen in pancreatic NETs as opposed to pulmonary tumors. For example, the oral multikinase inhibitor, sunitinib, which is active against multiple angiogenic pathways was tested in 107 patients with advanced NETs (26). Of these, 37 had carcinoids cancers, 14 of which were from the “foregut” which includes the lungs and stomach. In the carcinoid group, 44% of patients had tumor shrinkage, though most represented stable disease, with more activity noted in those with pancreatic NETs. The authors concluded that without further study it is difficult to clearly determine the efficacy of sunitinib in carcinoid tumors. Currently, there is no evidence to support the use of antiangiogenic agents in pulmonary NETs outside of a clinical trial.
Somatostatin Analogues
Somatostatin is a naturally occurring peptide that inhibits the release of growth hormone and multiple GI hormones. SSAs, such as octreotide, lanreotide, and pasireotide, are most commonly used to treat the symptoms associated with carcinoid syndrome. Cushing syndrome, which occurs in 1% to 6% of pulmonary WD-NETs does not respond to SSAs, but can be treated with ketoconazole, aminoglutethimide, metyrapone, or mifeprisonte (9). Acromegaly secondary to paraneoplastic growth hormone releasing hormone secretion is rare in NETs, but usually responds to SSAs or surgical tumor debulking (9). SSAs typically have a tolerable side-effect profile, though they can cause GI symptoms, and a small risk of hyperglycemia or cholelithiasis. Long acting formulations of SSAs should be considered as first-line treatment in functional WD-NETs as these agents can be extremely helpful for symptom control.
In GI NETs, SSAs have also been shown to inhibit tumor growth and can therefore be utilized as active anticancer treatment. The most frequently studied long-acting SSAs are octreotide-LAR and lanreotide, which are available as once-a-month injections in intramuscular or subcutaneous formulations. The U.S. FDA has approved two SSAs, octreotide and lanreotide, based on the results of randomized phase III trials that demonstrated improved antitumor activity versus placebo in nonpulmonary NETs (29,30). For example, in one study, median PFS was 14.3 for octreotide versus 6 months for placebo (P < .001), although overall survival was similar in both groups. Unfortunately, these trials explicitly excluded pulmonary NETs, so the potential antiproliferative effect in this setting remains unclear. A randomized phase II study is currently underway to assess lanreotide versus placebo in selected pulmonary and thymic NETs with positive receptor uptake on octreotide scan.
Radiotherapy and Radionuclides
Pulmonary NETs are relatively radiotherapy-resistant, and radiotherapy should typically only be considered when surgery is not feasible, after an incomplete resection, or for palliation of focal tumor-associated symptoms, such as painful bone metastases (5).
Radiolabeled SSAs have demonstrated effectiveness in small studies, but are not widely available. For example, PRRT technology links the radionuclides yttrium-90 or lutetium-177 to an SSA in order to target somatostatin-receptor-expressing tumor cells. The largest study of such therapy was a phase II trial of 90Y-DOTA-Tyr-octreotide in 1,109 patients with 25 different NET subtypes, including 84 who had pulmonary NETs with a positive octreotide scan (31). A “morphologic response” was reported in 34% of patients in the overall study population, though the majority of these patients were not evaluable by RECIST criteria. While intriguing, this treatment has considerable toxicity with 9% of patients experiencing permanent, grade 4 to 5 renal toxicity. The use of radiopeptides remains investigational and is unavailable in North America for pulmonary WD-NETs, although it is widely accepted as a treatment for GI NETs.
Directed Therapy for Metastatic Sites
The liver is the primary metastatic site for WD-NETs, and liver dysfunction due to metastatic involvement is the most frequent cause of death for patients with BPCs (5,8). Both the NCCN and IASLC guidelines suggest that surgical intervention may be attempted for curative intent in patients with indolent behaving pulmonary WD-NETs and limited hepatic metastases. However, this strategy is an extrapolation from the experience with GI NETs and it is not clear that it would be curative or even beneficial in patients with a pulmonary WD-NET since liver metastases in lung malignancies indicate systemic (rather than portal) hematogenous spread (17). In symptomatic patients with functional cancers, consideration of noncurative surgical debulking can be considered (17). Local tumour control via radiofrequency ablation (RFA), stereotactic radiotherapy, hepatic arterial chemoembolization, or radioisotope yttrium-90 eluting beads may also be considered on an individual basis, primarily for management of symptomatic metastases.
In summary, surgery can palliate symptoms and may provide a survival benefit for patients with GI NETs, but no evidence exists to support the use of surgical debulking or targeted ablation of metastases in pulmonary WD-NETs.
MANAGEMENT OF LCNEC
LCNEC was first identified as a distinct entity in 1991 and remains a relatively rare diagnosis (32). Currently, there is no standard treatment for pulmonary LCNEC, and there is an ongoing debate as to whether LCNEC should be managed using SCLC or NSCLC regimens. From a practical perspective, the general algorithm for treating LCNEC, particularly early stage disease, is the same as that for NSCLC, but the preferred chemotherapy regimens are the same as those used for SCLC.
Early Stage LCNEC
Surgery
Similar to NSCLC, stage I to II LCNEC is best treated with surgical resection with curative intent (33). Unfortunately, many patients are not surgical candidates since approximately 40% have distant metastatic disease and 60% to 80% have mediastinal lymph node involvement at time of diagnosis (34). Although there have been no randomized trials assessing methods of surgical resection for LCNEC, lobectomy with mediastinal lymph node sampling or dissection is the most frequently performed procedure, achieving an R0 resection in 84% to 100% (35–40). In summary, early stage (stage I–II) LCNEC should be treated like NSCLC and considered for complete surgical resection after appropriate preoperative evaluation as noted previously.
Adjuvant Therapy
There is little evidence of benefit from adjuvant chemotherapy or radiotherapy after complete resection of LCNEC. The majority of the data comes from retrospective studies in which approximately one-third of patients underwent adjuvant chemotherapy (Table 13.3) (35–40). In 2006, Iyoda et al. conducted a small prospective, single-armed, phase II trial of 15 patients with surgically resected LCNEC (35). Eleven patients had stage I disease. Patients were given two cycles of adjuvant cisplatin plus etoposide within 60 days of surgery. The outcomes of these patients were compared to 23 retrospectively identified patients with comparable characteristics who did not undergo adjuvant chemotherapy. There was a significant difference in survival between the two groups, with a better 5-year overall survival rate in adjuvantly treated patients (88% vs. 47%). Although this survival rate with adjuvant chemotherapy is quite high compared to that of other studies (28%–89%), this was the first demonstration of a potential survival benefit with the use of adjuvant chemotherapy in LCNEC. The same investigators later published their retrospective observations of a larger cohort of 72 patients with stage IA to IV LCNEC, 30 who received platinum-based adjuvant chemotherapy and 42 who did not (36). Most patients had recurrence within 3 years of surgery (91.7%) and the incidence of brain metastases was high. In a multivariate analysis, disease stage and the use of adjuvant chemotherapy emerged as independent prognostic variables with patients who received adjuvant therapy having a lower rate of tumor recurrence and a longer DFS (59% vs. 33%).
Sarkaria et al. retrospectively examined the survival of 93 patients with LCNEC, mostly with stage I to II disease; 22 received neoadjuvant platinum-based therapy and 71 received adjuvant treatment (39). Survival was similar with both treatment approaches, suggesting that in some cases neoadjuvant therapy may be a reasonable consideration. A prospective, randomized, double blind, phase III clinical trial is ongoing in Japan comparing adjuvant cisplatin plus irinotecan to cisplatin plus etoposide for patients with resected stage I to IIIA LCNEC. The choice of chemotherapy in this study reflects the standards for SCLC, particularly in Japan (41).
In summary, retrospective studies and extrapolation from prospective trials in NSCLC suggest that adjuvant chemotherapy could be beneficial for patients with completely resected stage II to III LCNEC. It is difficult to recommend adjuvant therapy for stage I LCNEC since this is not the standard of care for NSCLC and LCNEC does not typically respond to chemotherapy as well as SCLC does. Although the optimal regimen has not been defined, cisplatin plus etoposide has been the most commonly used combination because of the histological similarity to SCLC. Beyond the choice of chemotherapy, LCNEC is not generally treated like SCLC. For example, prophylactic cranial irradiation is not used in the adjuvant setting. The role of adjuvant radiation for resected N2 disease remains undefined and will likely follow whatever emerges as standard for NSCLC once more definitive trials have been completed. We do recommend that patients be referred to medical oncology for consideration of adjuvant therapy and that treatment decisions be made on a case-by-case basis with multidisciplinary input given the poor prognosis and high risk of recurrence (40%–60%) associated with LCNEC.
Locally Advanced LCNEC
Patients with locally advanced, unresectable stage III LCNEC are treated in a similar fashion as those with stage III NSCLC or limited-stage SCLC with four cycles of platinum-based chemotherapy plus concurrent definitive radiotherapy given with curative intent.
Metastatic LCNEC
Chemotherapy
Advanced LCNEC has a poor prognosis, and treatment is based primarily on small or retrospective studies. However, there is general agreement that platinum-based regimens do convey some advantage (Table 13.4). Three retrospective studies of systemic therapy have been conducted in patients with advanced LCNEC. Rossi et al. conducted a retrospective analysis of 83 patients with LCNEC across a broad range of stages. Regardless of stage, patients who received a “SCLC-like regimen” (primarily platinum plus etoposide) fared better than those who received a variety of typical “NSCLC regimens.” In the small group of patients with metastatic disease, 12 received a SCLC regimen and 15 a NSCLC regimen, with a higher response rate and a survival advantage noted for the SCLC treatment group (51 vs. 21 months; P < .001) (38).
In slight contrast, Sun et al. conducted a retrospective review of 45 consecutive patients with advanced LCNEC comparing the SCLC regimen of cisplatin plus etoposide (n = 11) against a variety of NSCLC regimens, including two patients treated with EGFR-directed therapy (42). Overall response rates were similar in both groups (SCLC regimen = 73% vs. NSCLC regiment = 50%; P = .19). Interestingly, there was an overall survival trend favoring the SCLC-treatment group (median, 16.5 vs. 9.2 months; P = .10).
Two small, single-arm, prospective phase II studies have been conducted in patients with advanced LCNEC examining cisplatin plus either etoposide or irinotecan. Le Treut et al. enrolled 42 patients with a centrally confirmed diagnosis of stage III or IV LCNEC on a phase II study of cisplatin plus etoposide for six cycles (43). Central pathology review reclassified 11 patients as having SCLC or another diagnosis other than LCNEC, highlighting one of the major challenges of drawing conclusions from studies in this disease entity. In the subgroup of 29 evaluable patients with confirmed LCNEC, 31% had a partial response and 34% had stable disease, with a median PFS of 5 months and median overall survival of 8 months. Another prospective phase II trial of 44 patients with advanced LCNEC assessed cisplatin plus irinotecan for four cycles (44). Again, 25% of patients were reclassified as SCLC. The response rate in patients with confirmed LCNEC was 47% with a median PFS of 5.8 months and a median overall survival of 12.6 months. Although the results of these prospective trials are not as encouraging as those from retrospective studies, they are likely more reflective of the reality of LCNEC, a disease that is nearly as aggressive as SCLC, but is as poorly responsive to therapy as NSCLC.
In summary, we recommend that metastatic LCNEC should be treated with one of the platinum-based chemotherapy regimens typically used to treat SCLC. Close attention should be paid to the potential side effects of therapy, since stage IV LCNEC is an incurable disease and maintenance of quality-of-life is a primary goal of care.
Molecularly Targeted Therapy
Despite the recent advances in targeted therapy and genomic profiling in NSCLC, there are little data to support the use of any specific targeted treatment in patients with LCNEC. Case reports suggest that EGFR activating mutations can occur in LCNEC and that these patients may respond to EGFR tyrosine kinase inhibitors, but such events appear to be rare (45).
Since LCNEC is a NET, Filosso et al. evaluated the use of adjuvant octreotide alone or in combination with radiotherapy in 10 patients with completely resected stage IB to IIIA LCNEC who had a positive preoperative octreotide scan (46). While there were some suggestions of a survival advantage with octreotide, the limitations of this study preclude any conclusion as to the activity of octreotide in this setting. Given the dearth of evidence supporting any specific targeted agent for patients with LCNEC, we strongly encourage participation in clinical trials.
